Abstract

BACKGROUND:

Men and women differ in their ability to extinguish fear. Fear extinction requires the activation of brain regions, including the ventromedial prefrontal cortex (vmPFC) and amygdala. Could estradiol modulate the activity of these brain regions during fear extinction?

METHODS:

All rat experiments were conducted in naturally cycling females. Rats underwent fear conditioning on Day 1. On Day 2, they underwent extinction training during the metestrus phase of the cycle (low estrogen and progesterone). Extinction recall was assessed on Day 3. Systemic injections of estrogen receptor-beta and -alpha agonists and of estradiol were administered at different time points to assess their influence on extinction consolidation and c-Fos expression in the vmPFC and amygdala. In parallel, healthy naturally cycling women underwent an analogous fear conditioning extinction training in a 3T functional magnetic resonance scanner. Measurement of their estradiol levels and skin conductance responses were obtained throughout the experiment.

RESULTS:

In female rats, administration of the estrogen-receptor beta (but not alpha) agonist facilitated extinction recall. Immediate (but not delayed) postextinction training administration of estradiol facilitated extinction memory consolidation and increased c-Fos expression in the vmPFC while reducing it in the amygdala. In parallel, natural variance in estradiol in premenopausal cycling women modulated vmPFC and amygdala reactivity and facilitated extinction recall.

CONCLUSIONS:

We provide translational evidence that demonstrates the influence of endogenous and exogenous estradiol on the fear extinction network. Our data suggest that women's endogenous hormonal status should be considered in future neurobiological research related to anxiety and mood disorders.

Extinction recall testing following estradiol administration led to decreased c-fos mRNA expression in amygdala and increased c-fos expression in the vmPFC

As shown in the diagram, these rats underwent the same testing procedure as those in experiments 1 and 2. Extinction learning took place and injections were administered, as in experiments 1 and 2, while rats were in the metestrus phase (bars show average relative gene expression +/− S.E., *p < 0.01).

Women in the high estradiol group (H-EST) show increased extinction retention relative to the low estradiol group (L-EST)

A) Skin conductance response (SCR) during extinction recall for women in the high estradiol group relative to the low estradiol group (H-EST vs. L-EST). Contrast compares first four trials of CS+E (extinguished cue) minus first four trials of CS+NE (non-extinguished cue). The H-EST group displayed significantly lower SCRs relative to the L-EST group during extinction recall, suggesting facilitated extinction memory expression in the H-EST group. B) Percent extinction retention in H-EST group versus L-EST group comparing CS+E to CS+NE. C) Regression plot between percent extinction retention and estradiol levels across all women (n = 32). Two subjects were excluded from these analyses as an outlier due to SCR responses that were three standard deviations beyond the mean. *p < 0.05.